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Clonal hematopoiesis (CH)—age-related expansion of mutated hematopoietic clones—can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk. Types of clonal hematopoiesis (CH) differ in frequency and fitness. These findings uncover shared genetic architecture, suggest evolutionary trade-offs between CH types, and detail elevated leukemia risk in individuals with overlapping types of CH. [ABSTRACT FROM AUTHOR]

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) in CDKN2A. However, it is unclear what role this gene or other genes play in its etiology. MATERIALS AND METHODS: We analyzed 189 cancer predisposition genes using parametric rare-variant association (RVA) tests and nonparametric permutation tests to identify gene-level associations in PDAC for patients with (CDKN2A +) and without (CDKN2A–) GPV. Exome sequencing was performed on 84 patients with PDAC, 47 CDKN2A+ and 37 CDKN2A–. After variant filtering, various RVA tests and permutation tests were run separately by CDKN2A status. Genes with the strongest nominal associations were evaluated in patients with PDAC from The Cancer Genome Atlas and the UK Biobank (UKB). A secondary analysis including only GPV from UKB was also performed. RESULTS: In RVA tests, ERCC4 and RET showed the most compelling evidence as plausible PDAC candidate genes for CDKN2A+ patients. In contrast, the findings in CDKN2A– patients provided evidence for HMBS , EPCAM , and MRE11 as potential new candidate genes and confirmed ATM, BRCA2 , and PALB2 as PDAC genes, consistent with findings in The Cancer Genome Atlas and the UKB. As expected, CDKN2A– patients were more likely to harbor GPVs from the 189 genes investigated. When including only GPVs from UKB, significant associations with PDAC were seen for ATM, BRCA2, and CDKN2A. CONCLUSION: These results suggest that variants in other genes likely play a role in PDAC in all patients and that PDAC in CDKN2A+ patients has a distinct etiology from PDAC in CDKN2A– patients. Our study reports on the complex genetics of #pancreaticcancer in an international cohort of patients with and without germline pathogenic variants in the CDKN2A gene. [ABSTRACT FROM AUTHOR]

Background: Mosaic chromosomal alterations (mCAs) are large chromosomal gains, losses and copy-neutral losses of heterozygosity (LOH) in peripheral leukocytes. While many individuals with detectable mCAs have no notable adverse outcomes, mCA-associated gene dosage alterations as well as clonal expansion of mutated leukocyte clones could increase susceptibility to disease. Results: We performed a phenome-wide association study (PheWAS) using existing data from 482,396 UK Biobank (UKBB) participants to investigate potential associations between mCAs and incident disease. Of the 1290 ICD codes we examined, our adjusted analysis identified a total of 50 incident disease outcomes associated with mCAs at PheWAS significance levels. We observed striking differences in the diseases associated with each type of alteration, with autosomal mCAs most associated with increased hematologic malignancies, incident infections and possibly cancer therapy-related conditions. Alterations of chromosome X were associated with increased lymphoid leukemia risk and, mCAs of chromosome Y were linked to potential reduced metabolic disease risk. Conclusions: Our findings demonstrate that a wide range of diseases are potential sequelae of mCAs and highlight the critical importance of careful covariate adjustment in mCA disease association studies. [ABSTRACT FROM AUTHOR]

Telomeres are DNA-protein structures at the ends of chromosomes essential in maintaining chromosomal stability. Observational studies have identified associations between telomeres and elevated cancer risk, including hematologic malignancies; but biologic mechanisms relating telomere length to cancer etiology remain unclear. Our study sought to better understand the relationship between telomere length and cancer risk by evaluating genetically-predicted telomere length (gTL) in relation to the presence of clonal somatic copy number alterations (SCNAs) in peripheral blood leukocytes. Genotyping array data were acquired from 431,507 participants in the UK Biobank and used to detect SCNAs from intensity information and infer telomere length using a polygenic risk score (PRS) of variants previously associated with leukocyte telomere length. In total, 15,236 (3.5%) of individuals had a detectable clonal SCNA on an autosomal chromosome. Overall, higher gTL value was positively associated with the presence of an autosomal SCNA (OR = 1.07, 95% CI = 1.05–1.09, P = 1.61×10−15). There was high consistency in effect estimates across strata of chromosomal event location (e.g., telomeric ends, interstitial or whole chromosome event; Phet = 0.37) and strata of copy number state (e.g., gain, loss, or neutral events; Phet = 0.05). Higher gTL value was associated with a greater cellular fraction of clones carrying autosomal SCNAs (β = 0.004, 95% CI = 0.002–0.007, P = 6.61×10−4). Our population-based examination of gTL and SCNAs suggests inherited components of telomere length do not preferentially impact autosomal SCNA event location or copy number status, but rather likely influence cellular replicative potential. Author summary: Telomeres lie at the ends of chromosomes and protect from damage and chromosomal fusions. Recent studies have identified relationships between telomere length and cancer risk; however, exactly how telomere length impacts cancer risk is unknown. We investigated potential associations between telomere length and somatic copy number alterations (SCNAs), as SCNAs are associated with cancer risk and may be responsible for some of the observed association between telomere length and cancer. We analyzed blood-derived DNA from over 430,000 participants in a large UK based study and identified an association between elevated telomere length (as inferred from genetic variants) and increased frequency of SCNAs. We did not find any difference in the relationship between telomere length and SCNAs based on specific regions of chromosomes impacted or whether chromosomes were lost or gained. However, we did note that longer predicted telomere length is associated with higher proportions of cells containing a SCNA. Although further studies are needed, our results provide new evidence indicating SCNAs may be a potential mechanism by which telomere length could impact cancer risk. [ABSTRACT FROM AUTHOR]

Age-related clonal expansion of cells harbouring mosaic chromosomal alterations (mCAs) is one manifestation of clonal haematopoiesis. Identifying factors that influence the generation and promotion of clonal expansion of mCAs are key to investigate the role of mCAs in health and disease. Herein, we report on widely measured serum biomarkers and their possible association with mCAs, which could provide new insights into molecular alterations that promote acquisition and clonal expansion. We performed a cross-sectional investigation of the association of 32 widely measured serum biomarkers with autosomal mCAs, mosaic loss of the Y chromosome, and mosaic loss of the X chromosome in 436 784 cancer-free participants from the UK Biobank. mCAs were associated with a range of commonly measured serum biomarkers such as lipid levels, circulating sex hormones, blood sugar homeostasis, inflammation and immune function, vitamins and minerals, kidney function, and liver function. Biomarker levels in participants with mCAs were estimated to differ by up to 5% relative to mCA-free participants, and individuals with higher cell fraction mCAs had greater deviation in mean biomarker values. Polygenic scores associated with sex hormone binding globulin, vitamin D, and total cholesterol were also associated with mCAs. Overall, we observed commonly used clinical serum biomarkers related to disease risk are associated with mCAs, suggesting mechanisms involved in these diseases could be related to mCA proliferation and clonal expansion., (Published by Oxford University Press 2023.)

Mosaic loss of Y chromosome (mLOY) is the most frequently detected somatic copy number alteration in leukocytes of men. In this study, we investigate blood cell counts as a potential mechanism linking mLOY to disease risk in 206,353 UK males. Associations between mLOY, detected by genotyping arrays, and blood cell counts were assessed by multivariable linear models adjusted for relevant risk factors. Among the participants, mLOY was detected in 39,809 men. We observed associations between mLOY and reduced erythrocyte count (-0.009 [-0.014, -0.005] × 10 12 cells/L, p = 2.75 × 10 -5 ) and elevated thrombocyte count (5.523 [4.862, 6.183] × 10 9 cells/L, p = 2.32 × 10 -60 ) and leukocyte count (0.218 [0.198, 0.239] × 10 9 cells/L, p = 9.22 × 10 -95 ), particularly for neutrophil count (0.174 × [0.158, 0.190]10 9 cells/L, p = 1.24 × 10 -99 ) and monocyte count (0.021 [0.018 to 0.024] × 10 9 cells/L, p = 6.93 × 10 -57 ), but lymphocyte count was less consistent (0.016 [0.007, 0.025] × 10 9 cells/L, p = 8.52 × 10 -4 ). Stratified analyses indicate these associations are independent of the effects of aging and smoking. Our findings provide population-based evidence for associations between mLOY and blood cell counts that should stimulate investigation of the underlying biological mechanisms linking mLOY to cancer and chronic disease risk.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism 1-5 , yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.

Mosaic loss of the Y chromosome (mLOY) in peripheral leukocytes is a somatic event in which a fraction of leukocytes have lost the entire Y chromosome. The frequency of mLOY increases with age and may reflect poor genomic maintenance as well as clonal imbalances in normal immune function, making mLOY an attractive candidate marker for cancer risk. Here, we investigated the relationship between mLOY and incident cancer in a large sample of 207,603 cancer-free men from the UK Biobank, in which 13,895 men developed an incident solid tumor during follow-up. We identified mLOY by scanning for deviations in genotyping array log R intensity ratios across the male-specific chromosome Y region. Overall, we detected low proportions of cells with mLOY in 3,358 (1.6%) men and high proportions of mLOY in 524 (0.3%) men. We found an association of mLOY with overall solid tumor incidence using both low and high mLOY thresholds [HR low = 1.18; 95% confidence interval (CI) low , 1.07-1.30; P low = 0.001; HR high = 1.36; 95% CI high , 1.09-1.71; P high = 0.007] and more specifically we observed an association with lung cancer (HR high = 2.25; 95% CI high , 1.36-3.71; P high = 0.002). Stronger associations were observed without adjustment for smoking, suggesting that smoking is an important confounder of tumor incidence. It is unlikely that mLOY is a major mediator of the effect of cigarette smoking on cancer risk, as mLOY was observed in only a small fraction of smokers who developed cancer. In summary, mLOY was modestly associated with incidence of solid tumors in the UK Biobank, although for some cancer subtypes these findings may reflect residual confounding by smoking. SIGNIFICANCE: Evidence from the UK Biobank indicates mosaic chromosome Y loss in leukocytes is moderately associated with increased incidence of select solid tumors., (©2018 American Association for Cancer Research.)

Background: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR)., Methods: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium., Results: Thirty-five metabolites were strongly associated with prostate cancer ( P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal., Conclusions: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk., Impact: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification., (©2018 American Association for Cancer Research.)

Mosaic loss of the Y chromosome (mLOY) is the most commonly reported large structural somatic event. Previous studies have indicated age and cigarette smoking increase the risk of mLOY, but the relationship of other exposures with mLOY and mLOY with disease has not been adequately investigated. We characterized mLOY in a large cohort of 223,338 men from the UK Biobank by scanning for deviations in genotyping array median log 2 intensity ratios (mLRR) of the Y chromosome using a standard algorithm. A total of 3,789 (1.7%) men showed evidence for mLOY (mLRR < -0.15). In multivariable-adjusted logistic regression models, we found that mLOY increases exponentially with age (overall P-value < 4.9 × 10 -324 ; p-value for the quadratic term = 2.1 × 10 -7 ), and observed a strong association with current smoking (P-value = 7.8 × 10 -184 ). We observed less mLOY in men of African ancestry (0.4%) compared to men of European ancestry (1.8%, P-value = 0.003). Although mLOY was not associated with prevalent cancer (P-value = 0.61), associations were observed for diabetes (P-value = 0.003) and cardiovascular disease (P-value = 0.01). Using Cox proportional hazards regression models, mLOY was associated with all-cause mortality among men with a high proportion of cells affected (mLRR < -0.40; HR = 1.35, 95% CI = 1.08-1.70, P-value = 0.009). In conclusion, mLOY was associated with several health-related factors as well as with all-cause mortality. Further functional studies are warranted to understand how and in what way mLOY could influence adult male health.

Background: Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered., Methods: We compared 296,114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11,880 case subjects and 12,487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I(2) statistics. All statistical tests were two-sided., Results: We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 × 10(-10)). This single-nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel-like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 × 10(-7); rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 × 10(-7)). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 × 10(-6))., Conclusions: These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects.